Two current issues in drug delivery concern the spatial and temporal attributes of therapeutic delivery systems. Targeting the therapeutic to limit its exposure to the desired site of action is the spatial aspect. Controlling the delivery of the therapeutic over time is the temporal aspect. Continuous drug release often is preferable to periodically administering bolus doses to the entire organism. Bolus administration results in a spike of drug concentration, followed by a decrease in concentration to baseline.
Moreover, patients often fail to comply with bolus drug administration procedures, one example being outpatients who do not complete their course of antibiotics. This is a key problem in controlling emerging drug-resistant strains of tuberculosis, and is probably a factor contributing to an increase in the appearance of many other drug-resistant strains of bacteria. The cost in morbidity and mortality from inadequate frequency of dosing with insulin is known to be in the billions of dollars in the United States alone. Reach et al.'s Can Continuous Glucose Monitoring be used for the Treatment of Diabetes, 64:381A-386A (Analytical Chemistry, 1992). Restricting ambulatory patients to a hospital setting to insure compliance (or establishing some other system of enforced compliance) is not a practical solution. Patient noncompliance with bolus administration procedures therefore is an important impetus for developing continuous drug delivery systems.
At present there are several approaches to controlled or continuous drug delivery, some of which are still in the research phases, and some of which have been successfully used in commercial products for some time. Prevost et al.'s New Methods of Drug Delivery, 249:1527-1533 (Science, 1990). The delivery approaches include: (1) external delivery systems, such as external mechanical pumps and osmotic patches; (2) internal osmotic pumps; and (3) implantable or ingestible polymeric structures that can include erodible hydrogels. With pumps, continuous release can be set by the pump design or by controlling the motor. Continuous drug delivery using continuous infusion with an i.v. line (the only viable method for some chemotherapeutic drugs) is costly and restricts the patient's movement. Implanted catheters and pumps are an expensive solution, the considerable risk of which is only balanced by the importance of continuous delivery of the drug in question. Using implantable macroscopic devices for drug delivery restricts the site of delivery to one that can accommodate the object. The NORPLANT.RTM. contraceptive system, effective though it is, requires a large insertion site and must be surgically recovered after use.
With polymeric structures the rate of delivery can be controlled by the shape and permeability-erodability of the polymer. Dermal patches are very simple and relatively noninvasive. However, dermal patches have been effective only for a few drugs that are relatively permeant through the skin.
Some of the approaches discussed above work well for some classes of drugs, and are inapplicable to others. The chemically labile nature of peptide drugs, for example, results in their incompatibility with many polymeric delivery systems. Those polymers in which they can be immobilized have yet to be approved for general use. And, the common feature of all the existing delivery systems listed above is that they control diffusion or effusion by a macroscopic mechanical object. This limits their usefulness and makes using the delivery systems a nuisance and perhaps even requires invasive surgical implanting.
Drug distribution can be controlled by the microstructures into which the drug self-assembles. Liposomes are one example of a self-assembled microstructure, and encapsulating drugs in liposomes has proven useful in some circumstances. Ostro, Liposomes: From Biophysics to Therapeutics, Marcel Dekker, Inc. (1987). For instance, liposomes can be used to deliver drugs to skin. Yager et al's Conjugation of Phosphatidyl-ethanolamine to poly(n-isopropylacrylamide) for Potential Use in Liposomal Drug Delivery Systems, 33:4659-4662 (Polymer, 1992). Phosphatidylglycerols have been modified with a wide range of peptide and non-peptide drugs (in particular AZT) with the assumption that they would self-assemble into liposomes, and would be trapped by macrophages in the reticuloendothelial system after injection into the bloodstream. Wang et al.'s Synthesis of Phospholipid-Inhibitor Conjugates by Enzymatic Transphospha-tidylations with Phospholipase D, 115:10487-10491 (J. Am. Chem. Soc., 1993). Beyond the general assumption that liposomes would be formed, how hydrophobically modified drugs self-associate, and how the self-association affects the conformation of the drugs themselves, is largely unknown.
Lipid tubules are a recently discovered self-organizing system in which lipids crystallize into tightly packed bilayers that spontaneously form hollow cylinders less than 1 .mu.m in diameter. The basic subunit of the tubule is a helical ribbon of lipid bilayer and, in some cases, open helical structures of the same diameter can be seen. In 1983, polymerizable diacetylenic phosphatidylcholines such as 1,2-di-(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (referred to as DC.sub.8,9 PC) were discovered by Yager and Schoen to form novel hollow tubular microstructures. See, for instance, Yager et al.'s Formation of Tubules by a Polymerizable Surfactant, 106:371-381 (Mol. Cryst. Liq. Cryst., 1984). Diacetylenic lipid tubules are straight, rigid, about 0.75 .mu.m in diameter, and can be made to range in length from a few pm to nearly 1 mm, depending on the conditions used to form the microstructure. Further, the walls of the tubules may be as thin as a single bilayer. The lumen (the open space in a tubular organ or device) is generally open, allowing free access by diffusion from the ends of the microstructures.
Kunitake et al. demonstrated that a positively charged chiral amphiphile based on glutamate forms structures similar to those formed by DC.sub.8,9 PC. Kunitake et al.'s Helical Superstructures are Formed from Chiral Ammonium Bilayer Membranes, 1709-1712 (Chem. Lett., 1984). Helices and tubules of much smaller diameters (.about.300 .ANG.) were found by Yamada et al. to form from related synthetic two-chain amphiphiles with oligopeptides (such as 12-14-mers of glutamic and aspartic acid) as hydrophilic headgroups. Yamada et al.'s Formation of Helical Super Structure from Single-Walled Bilayers by Amphiphiles with Oligo-L-Glutamic Acid-Head Group, 10:1713-1716 (Chem. Lett., 1984). Yamada et al.'s Amphiphiles with Polypeptide head Groups. 7. Relationship Between Formation of Helical Bilayer membranes and Chemical Structures of Dialkyl Amphiphiles with Polypeptide-Head Groups, 48:327-334 (Kobunshi Ronbunshu, 1991). Recent work by Shimizu and Hato on similar lipids with polypeptide headgroups, including (Pro).sub.3 -tripeptide, produced similar tubules and helices. Later studies by the Yamada group ascertained that both positive, negative and neutral amino acids could be incorporated into block copolymers as headgroups for glutamate-based lipopeptides.
However, fully charging the headgroups prevented tubule and helix formation. This is presumably because charging the polypeptide side chains increases the headgroup excluded volume to the point that close packing of the hydrocarbon chains is no longer possible in a planar bilayer. Further, there was evidence that the secondary structure of the polypeptide varied with the nature of the microstructure and that .beta.-sheet formed between headgroup polypeptides.
It recently was determined that helical and tubular structures, as well as rod-like cochleate cylinders, can be formed quantitatively from the n-fatty acyl and .alpha.-hydroxy fatty acyl fractions of bovine brain galactocerebrosides, designated NFA-cer and HFA-cer, respectively. Yager et al.'s Microstructural Polymorphism in Bovine Brain Galactocerebrosides and its Two Major Subfractions, 31:9045-9055 (Biochem., 1992). Tubular and helical structures have now bee(n observed in samples of aged suspensions of saturated-chain phosphatidylcholines and as transient intermediates in the crystallization of cholesterol from mixed micellar suspensions. See, for instance, Konikoff et al.'s Filamentous, Helical, and Tubular Microstructures During Cholesterol Crystallization from Bile, 90:1155-1160 (J. Clin. Invest., 1992).
There appear to have been no commercialized uses for tubules to date. Lipid tubules have been "decorated" with inorganic materials, including metals [See, for instance, Schnur et al.'s U.S. Pat. No. 4,911,981, entitled Metal Clad Lipid Microstructures] and salts [Yager et al.'s Formation of Mineral Microstructures with a High Aspect Ratio from Phospholipid Bilayer Tubules, 11:633-636 (J. Mat. Sci. Lett., 1992), although a practical use for these materials has not yet been reported. Some preliminary work has been undertaken to use the lumen of diacetylenic lipid tubules as a reservoir for the encapsulation of drugs for delivery in wound dressings. See, for instance, Cliff et al.'s The Use of Lipid Microcylinders as Release Vehicles; Release Rates of Growth Factors and Cytokines, Fourth World Biomaterials Conference (1992). These procedures have yet to realize and exploit the beneficial physical characteristics of tubules.
There also are patented approaches to using cochleate cylinders as drug delivery systems. For example, Mannino et al. have used cochleates cylinders, formed by the addition of calcium ions to some negatively charged phopholipids, to encapsulate materials. See, for example, U.S. Pat. Nos. 4,663,161 and 4,871,488, and international patent application, No. PCT/US96/01704. Mannino's cochleate cylinders apparently undergo a transformation to a liposomal intermediate prior to drug release.